Investigating the neurovascular coupling in the cerebellar granular layer.

The neurovascular coupling (NVC) or functional hyperemia is the mechanism whereby neuronal activity controls cerebral blood flow (CBF). The tight coupling between neuronal activation and blood vessels diameter modifications ensures the proper supply of oxygen and nutrients to the central nervous system. In the brain, CBF adaptations are governed by vasoactive agents and their action on the vascular system (Iadecola, 2017). This phenomenon is also involved in the genesis of the blood-oxygen-level-dependent (BOLD) signals used by neuroimaging techniques, like functional magnetic resonance imaging (fMRI), to map changes in brain activity. Although being highly investigated, the interpretation of activity-dependent BOLD responses is widely debated (Hall et al., 2016). The complexity of investigating BOLD neurophysiological basis, i.e. NVC mechanisms, resulted in the inability to define a comprehensive theory for BOLD signals interpretation. In this work of thesis, the attention was focused on NVC mechanisms in the cerebellum. In this region, NVC has been previously investigated in the molecular layer, where interneurons activation has been found as the main player, unlike Purkinje cells spiking activity (Cauli et al., 2004; Thomsen et al., 2004). Surprisingly, there was no information about the role of the granular layer in cerebellar NVC before our investigations. In the granular layer, NVC is mediated by granule cells through an NMDA receptor/NO-dependent system acting on pericytes (Mapelli et al., 2017). The latter are contractile cells able to regulate the caliber of brain capillaries (Attwell et al., 2016),which are thought to be involved in the genesis of BOLD signals (Hall et al., 2016). Recent investigations using human fMRI demonstrated that cerebellar vermis lobule V and hemisphere lobule VI showed respectively linear and non-linear BOLD responses during the same motor task performance (Alahmadi et al., 2017). In mouse cerebellar slices, vermis lobule V and hemisphere lobule VI responded with different non-linear neurovascular events to several frequency patterns of neuronal activation, suggesting that NVC and thus BOLD signals might be region-dependent in the cerebellum (Gagliano et al., 2018 in preparation). In conclusion, granule cells, pericytes and capillaries may drive the basic neurovascular mechanisms of the cerebellum, but different cerebellar regions (vermis and hemisphere) could differently contribute to the genesis of cerebellar BOLD signals. These results might reflect different functions of these cerebellar areas following the same input.